Thématique :
- Cancers autres (hors CCR et CHC)
- Pancréas/Voies biliaires
Originalité :
Solidité :
Doit faire évoluer notre pratique :
Dans certains cas
Nom du veilleur :
Professeur Sylvain MANFREDI
Coup de coeur :
Journal of the National Cancer Institute (JNCI)
  2016 Feb 8;108(5). pii: djv387  
  doi: 10.1093/jnci/djv387  
  Relevance of Sp Binding Site Polymorphism in WWOX for Treatment Outcome in Pancreatic Cancer  
  Markus A. Schirmer, Claudia M. Lüske, Sebastian Roppel, Alexander Schaudinn, Christian Zimmer, Ruben Pflüger, Martin Haubrock, Jacobe Rapp, Cenap Güngör, Maximilian Bockhorn, Thilo Hackert, Thomas Hank, Oliver Strobel, Jens Werner, Jakob R. Izbicki, Steven A. Johnsen, Jochen Gaedcke, Jürgen Brockmöller and B. Michael Ghadimi.  


A genome-wide association study (GWAS) suggested inherited genetic single-nucleotide polymorphisms (SNPs) affecting overall survival (OS) in advanced pancreatic cancer. To identify robust clinical biomarkers, we tested the strongest reported candidate loci in an independent patient cohort, assessed cellular drug sensitivity, and evaluated molecular effects.


This study comprised 381 patients with histologically verified pancreatic ductal adenocarcinoma treated with gemcitabine-based chemotherapy. The primary outcome was the relationship between germline polymorphisms and OS. Functional assays addressed pharmacological dose-response effects in lymphoblastoid cell lines (LCLs) and pancreatic cancer cell lines (including upon RNAi), gene expression analyses, and allele-specific transcription factor binding. All statistical tests were two-sided.


The A allele (26% in Caucasians) at SNP rs11644322 in the putative tumor suppressor gene WWOX conferred worse prognosis. Median OS was 14 months (95% confidence interval [CI] = 12 to 15 months), 13 months (95% CI = 11 to 15 months), and nine months (95% CI = 7 to 12 months) for the GG, GA, and AA genotypes, respectively (P trend < .001 for trend in univariate log-rank assuming a codominant mode of inheritance; advanced disease subgroup P trend < .001). Mean OS was 25 months (95% CI = 21 to 29 months), 19 months (95% CI = 15 to 22 months), and 13 months (95% CI = 10 to 16 months), respectively. This effect held true after adjustment for age, performance status according to Eastern Cooperative Oncology Group classification, TNM, grading, and resection status and was comparable with the strongest established prognostic factors in multivariable analysis. Consistently, reduced responsiveness to gemcitabine, but not 5-fluorouracil, along with lower WWOX expression was demonstrated in LCLs harboring the AA genotype. Likewise, RNAi-mediated WWOX knockdown in pancreatic cancer cells confirmed differential cytostatic drug sensitivity. In electrophoretic mobility shift assays, the A allele exhibited weaker binding of Sp family members Sp1/Sp3.


WWOX rs11644322 represents a major predictive factor in gemcitabine-treated pancreatic cancer. Decreased WWOX expression may interfere with gemcitabine sensitivity, and allele-specific binding at rs11644332 might be a causative molecular mechanism behind the observed clinical associations.

Question posée
Valeur pronostique et prédictive d’une mutation dans le cancer du pancréas.
Question posée
La mutation à l’état homozygote de WWOX rs11644322 confère un pronostic plus mauvais, par le biais d’une moins bonne réponse au traitement par Gemcitabine.

La recherche de cette mutation, si son effet prédictif est confirmé, nous permettra de mieux sélectionner les patients qui relèvent d’un traitement par Gemcitabine.